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Measurable residual disease in elderly acute myeloid leukemia: results from the PETHEMA-FLUGAZA phase III clinical trial

ABSTRACT: The value of measurable residual disease (MRD) in elderly patients with acute myeloid leukemia (AML) is inconsistent between those treated with intensive vs hypomethylating drugs, and unknown after semi-intensive therapy. We investigated the role of MRD in refining complete remission (CR) and treatment duration in the phase III PETHEMA-FLUGAZA clinical trial, that randomized 283 elderly AML patients to induction and consolidation with fludarabine plus cytarabine or induction and consolidation with 5-azacitidine. After consolidation, patients continued treatment if MRDÃ¢Â‰Â¥0.01% or stopped if MRD<0.01%, assessed by multidimensional flow cytometry (MFC). On multivariate analysis including genetic risk and treatment arm, MRD status in patients achieving CR (N=72) was the only independent prognostic factor for cumulative-incidence of relapse (HR:2.95;P=.002) and relapse-free survival (HR:3.45;P=.002). A trend for longer overall survival was observed in patients with undetectable MRD (N=13/72). Although leukemic cells from most elderly AML patients display phenotypic aberrancies vs their normal counterpart (N=258/265), CD34 progenitors from cases with undetectable MRD by MFC displayed extensive genetic abnormalities identified by whole-exome sequencing. This study supports MRD assessment to refine CR after semi-intensive therapy or hypomethylating agents, but unveils that improved sensitivity is warranted to individualize treatment and prolong survival of elderly AML patients achieving undetectable MRD.

PROVIDER: EGAS00001004574 | EGA |

REPOSITORIES: EGA

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Project description:During many years, chemo-immunotherapy fludarabine-cyclophosphamide-rituximab (FCR) was considered as the gold standard for the first line treatment of medically fit patients with symptomatic B-chronic lymphocytic leukemia (CLL). Over the last decade, targeted biotherapies have revolutionized the management of B-CLL patients' treatment and almost entirely supplanted FCR. However, no biomarker still exists to predict the complete remission (CR) with undetectable minimal residual disease (uMRD), which remains so far the best predictive factor for survival. Circulating miRNAs represent a class of molecular biomarkers which expression is altered in hematological disorders including B-CLL. Our present study aimed at identifying before treatment circulating miRNAs that predict the treatment outcome in previously untreated B-CLL patients (NCT 01370772, https://clinicaltrials.gov/ct2/show/NCT01370772). Using hierarchical clustering of miRNA expression profiles discriminating 8 patients who achieved CR with bone marrow (BM) uMRD, from 8 patients who do not achieved CR and displayed detectable BM MRD, we identified 25 miRNAs differentially expressed before treatment. The expression of 11 representative miRNAs was further validated on a larger cohort (n=123). Based on the dosage of 5 miRNAs at diagnosis, a decision tree was constructed to predict treatment outcome. Our results identified 6 groups of patients with a distinct probability of being CR with BM uMRD to FCR treatment, ranging from 72% (miR-125b, miR-15b and miR-181c high) to 4% (miR-125b and miR-193b low). Progression-free survival (PFS) was significantly different between the established groups (p=0.019). None of the patients displaying high expression levels of miR-125b, miR-15b and miR-181c (HHH group) relapsed during the follow-up of the study. In contrast, patients with miR-15b low and miR-412 high (HLH group), and patients with low expression levels of miR-125b and miR-193b (LL group) demonstrated a significant low PFS. By RNA sequencing blood at diagnosis, we compared mRNA expression profiles of these three groups, achieving or not CR with uMRD. We identified that patients relapsing after treatment are characterized by significant enrichment of gene signatures related to cell cycle, MYC target genes, metabolism and translation regulation at diagnosis. Conversely, patients achieving CR with uMRD displayed significant enrichment in genes related to communication between CLL cells and the microenvironment, immune system activation and upregulation of polycomb PRC2 complex target genes at diagnosis. Our results suggest that blood miRNAs are potent predictive biomarkers for treatment efficacy of FCR and might be implicated in the FCR efficacy in B-CLL patients. Further investigations could establish whether these miRNAs might also be used to stratify patients for new-generation treatments. Overall, our work provides insight into unmet need for the treatment of B-CLL patients and identified pathways potentially predictive of patients’ remission.

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Measurable residual disease in elderly acute myeloid leukemia: results from the PETHEMA-FLUGAZA phase III clinical trial

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